Formulations for use in inhaler devices

ABSTRACT

A formulation for an inhaler device comprises carrier particles having a diameter of at least 50 μm and a mass median diameter of at least 175 μm; active particles; and additive material to which is able to promote release of the active particles from the carrier particles on actuation of the inhaler device. The formulation has excellent flowability even at relatively high fine particle contents.

[0001] The invention relates to carrier materials for use in inhalerdevices, to formulations comprising the carrier materials and to the useof the formulations.

[0002] The administration of pharmacologically active agents byinhalation is a widely used technique, especially for the treatment ofdiseases of the respiratory tract. The technique is also used for theadministration of certain active agents having systemic action, whichare absorbed, via the lungs, into the bloodstream. Known inhaler devicesinclude nebulizers, pressurised metered dose inhalers and dry powderinhalers. The present invention is primarily concerned with formulationsfor use in dry powder inhalers, although in some circumstancesformulations according to this invention may also or instead be usefulin pressurised metered dose inhalers.

[0003] The delivery of dry powder particles of an active agent to therespiratory tract presents certain problems. The inhaler should deliverto the lungs the maximum possible proportion of the active particlesexpelled from the device, including a significant proportion to thelower lung, preferably even at the poor inhalation capabilities of somepatients, especially asthmatics. In use of many of the currentlyavailable devices, however, only a proportion, and frequently as littleas 10%, of the active particles expelled from the device on inhalationreach the lower lung.

[0004] On exit from the inhaler device, the active particles should forma physically and chemically stable aerocolloid which remains insuspension until it reaches an alveolar or other absorption site. Onceat the absorption site, the active particles should be capable ofefficient collection by the pulmonary mucosa with no active particlesbeing exhaled from the absorption site.

[0005] The size of the active particles is important. For effectivedelivery of active particles deep into the lungs, the active particlesshould be small, with an equivalent aerodynamic diameter substantiallyin the range of up to 10 μm. Small particles are howeverthermodynamically unstable due to their high surface area to volumeratio, which provides significant excess surface free energy andencourages particles to agglomerate. Agglomeration of small particles inthe inhaler and adherence of particles to the walls of the inhaler canresult in the active particles leaving the inhaler as large agglomeratesor in their not leaving the inhaler and remaining adhered to theinterior thereof.

[0006] The uncertainty as to the extent of agglomeration of theparticles between each actuation of the inhaler and between differentinhalers and different batches of particles, leads to poor dosereproducibility. It has been found that powders are generallyreproducibly fluidisable, and therefore reliably. removable from aninhaler device, when the particles have a diameter greater than 60 μm.Good flow properties are desirable in the contexts of metering and ofdispersal from the device.

[0007] To give the most effective dry powder aerosol, therefore, theparticles should be large while in the inhalers, but small when in therespiratory tract.

[0008] It is common, in an attempt to achieve those demands, to includein the dry powder formulation carrier particles, to which the activeparticles can adhere whilst in the device, the active particles thenbeing dispersed from the surfaces of the carrier particles on inhalationinto the respiratory tract, to give a fine suspension. It is known thatthe presence of a certain amount of fine excipient material, normally ofthe same material as the carrier, can improve the proportion of drugreaching the lung. The presence of such a fraction of fine excipient isconventionally limited to less than 10% and generally less than 5% dueto the catastrophic loss of flowability at higher fine particlecontents, leading to poor dose reproducibility.

[0009] The proportion of the active particles reaching the lung can beincreased by incorporating in the formulation an agent which promotesrelease of the active particle, as described in WO96/23485.

[0010] The invention provides a formulation for use in an inhalerdevice, comprising

[0011] carrier particles having a diameter of at least 50 μm and a massmedian diameter of at least 175 μm;

[0012] active particles; and

[0013] additive material which is able to promote release of the activeparticles from the carrier particles on actuation of the inhaler device.

[0014] The formulation of the invention surprisingly has both excellentflowability within the device and, on expulsion from the device, permitsgood dispersion of the active particles from the carrier particles andgeneration of a relatively high fine particle fraction, promotingdelivery of a relatively large proportion of the active particles intothe lung.

[0015] The use of carrier particles of relatively large size isdescribed in WO96/02231, but that document does not suggest theincorporation of additive material to promote release of the activeparticles from the carrier particles. The carrier particles used inaccordance with the present invention have a mass median diameter (MMD)of at least 175 μm. In fact, it is preferred that the MMD of the carrierparticles is at least 200 μm, and more preferably at least 250 μm.

[0016] The carrier particles have a diameter of at least 50 μm. Althoughas described below the formulation may include particles of diameterless than 50 μm of the same material as the carrier particles, thosesmaller particles are not included within the term “carrier particles”as used herein. Advantageously, not more than 10% by weight, andpreferably not more than 5% by weight, of the carrier particles have adiameter of 150 μm or less. Advantageously at least 90% by weight of thecarrier particles have a diameter of 175 μm or more, and preferably 200μm or more. Advantageously, at least 90% by weight, and preferably atleast 95% by weight, of the carrier particles have a diameter of notmore than 1 mm. Preferably at least 90% by weight of the carrierparticles have a diameter of not more than 600 μm. Advantageously, atleast 50% by weight, and preferably at least 60% by weight, of thecarrier particles have a diameter of 200 μm or more. Preferably, atleast 90% by weight of the carrier particles have a diameter between 150μm and 750 μm, more preferably between 150 μm and 650 μm. Particularadvantages are offered by formulations in which substantially all of thecarrier particles have a diameter in the range of about 210 to about 360μm or from about 350 to about 600 μm.

[0017] The carrier particles may be of any acceptable pharmacologicallyinert material or combination of materials. For example, the carrierparticles may be composed of one or more materials selected from sugaralcohols; polyols, for example sorbitol, mannitol and xylitol, andcrystalline sugars, including monosaccharides and disaccharides;inorganic salts such as sodium chloride and calcium carbonate; organicsalts such as sodium lactate; and other organic compounds such as urea,polysaccharides, for. example starch and its derivatives;oligosaccharides, for example cyclodextrins and dextrins. Advantageouslythe carrier particles are of a crystalline sugar, for example, amonosaccharide such as glucose or arabinose, or a disaccharide such asmaltose, saccharose, dextrose or lactose. Preferably, the carrierparticles are of lactose.

[0018] The carrier particles are preferably of a material having afissured surface, that is, on which there are clefts and valleys andother recessed regions, referred to herein collectively as fissures. Thefissures should preferably be a least 5 μm wide extending to at least 5μm deep, preferably at least 10 μm wide and 10 μm deep and mostpreferably at least 20 μm wide and 20 μm deep.

[0019] Because of the excellent flow properties of the formulationscontaining the fissured carrier particles, the formulations offerspecial advantages in the administration of active agents to beadministered in relatively large doses. Thus, whereas formulationscontaining conventional lactose carriers and fine particle contents ofabove 5% tend to have poor flow properties, with flow properties at fineparticle contents above 10% being very poor, the formulations of theinvention may have adequate flow properties even at fines contents (thatis contents of active particles and of any fine particles of additivematerial, together with any other particles of aerodynamic diameter ofnot more than 20 μm) of up to 90% by weight, based on the total weightof fines and carrier particles. Moreover, the fissured carrier particlesoffer particular advantages in that they are capable of retainingrelatively large amounts of fine material in the fissures without orwith only little segregation. That is thought to underly the goodrespirable fraction that is generated in use of the formulations and isespecially advantageous in use of the carrier particles with certainadditive materials, for example, magnesium stearate, which tend to causesegregation of the components, permitting increased amounts of suchadditive materials to be used without increasing segregation tounacceptable levels. Advantageously, the fines content is not more than50% by weight, and more preferably not more than 20% by weight, based onthe total weight of fines and carrier particles. Preferably, the finescontent is at least 5% by weight, based on the total weight of fines andcarrier particles. The invention. offers particular advantages in thecase of formulations containing at least 10%, for example, from 10 to20% by weight fines or at least 20%, for example from 20 to 50% byweight fines, in each case, based on the total weight of fines andcarrier particles. The fines content may include from 0.1 to 99% byweight active particles, for example from 0.1 to 90% by weight, andadvantageously from 0.1 to 80% by weight active particles, in each casebased on the total weight of fines. In many cases, however, the activeparticles will constitute less than half of the total weight of fines.

[0020] A number of methods may be used to determine whether carrierparticles have a fissured surface that will offer the above-mentionedcapability of retaining relatively large fines contents substantiallywithout segregation:

[0021] 1. Determination of tapped density.

[0022] The tapped density of the fissured carrier particles may be about6% or more, and preferably 15% or more, lower than the tapped density ofcarrier particles of the same material and of particle characteristicsof a kind typical of carrier particles which have conventionally beenused in the manufacture of inhalable powders. In the case of fissuredcarrier particles of crystalline sugars, for example lactose, the tappeddensity of the fissured particles is not more than 0.75 g/cm³, andpreferably not more than 0.70 g/cm³. The tapped density of lactosegrades conventionally used in the manufacture of commercial DPIformulations is typically about 0.8 g/cm³. Tapped densities referred toherein may be measured as follows:

[0023] A measuring cylinder is weighed on a top pan balance (2 place).Approximately 50 g powder is introduced into the measuring cylinder, andthe weight is recorded. The measuring cylinder containing the powder isattached to a jolting volumeter (Jel Stampfvolumeter). The joltingvolumeter is set to tap 200 times. During each tap, the measuringcylinder is raised and allowed to fall a set distance. After the 200taps, the volume of the powder is measured. The tapping is repeated andthe new volume measured. The tapping is continued until the powder willsettle no more. The tapped density is calculated as the weight of thepowder divided by the final tap volume. The procedure is performed threetimes (with new powder each time) for each powder measured, and the meantapped density calculated from those three final tapped volume values.

[0024] 2. Mercury Intrusion Porosimetry. Mercury intrusion porosimetryassesses the pore size distribution and the nature of the surface andpore structure of the particles. Porosimetry data is suitably collectedover pressure range, 3.2 kPa to 8.7 MPa, for example, using an Autopore9200 II Porosimeter (Micromeritics, Norcross, USA). Samples should beevacuated to below 5 Pa prior to analysis to remove air and looselybound surface water. Suitable lactose is characterised by a bulk densityof not more than 0.65 g/cm³ and preferably not more than 0.6 g/cm³.Suitable lactose is also characterised by a total intrusion volumemeasured by mercury intrusion porosimetry of at least 0.8 cm³g⁻¹ andpreferably at least, 0.9 cm³g⁻¹. (It has been found that lactose havinga bulk density of 0.6 g/cm³ as measured by mercury intrusion porosimetryhas a tapped density of about 0.7 g/cm³, whereas the discrepancy betweenthe two methods at lower densities is less.)

[0025] 3. “Fissure Index”. The term “fissure index” used herein refersto the ratio of a theoretical envelope volume of the particles, ascalculated from the envelope of the particles, to the actual volume ofthe particles, that is, omitting fissures within the envelope. Suitableparticles are those having a fissure index of at least 1.25. Thetheoretical envelope volume may be determined optically, for example, byexamining a small sample of the particles using an electron microscope.The theoretical envelope volume of the particles may be estimated viathe following method. An electron micrograph of the sample may bedivided into a number of grid squares of approximately equalpopulations, each containing a representative sample of the particles.The population of one or more grids may then be examined and theenvelope encompassing each of the particles determined visually asfollows. The Feret's diameter for particles within a grid is measuredrelative to a fixed axis of the image. Typically at least ten particlesare measured for their Feret's diameter. Feret's diameter is defined asthe length of the projection of a particle along a given reference lineas the distance between the extreme left and right tangents that areperpendicular to the reference line. A mean Feret's diameter is derived.A theoretical mean envelope volume may then be calculated from this meandiameter to give a representative value for all the grid squares andthus the whole sample. Division of that value by the number of particlesgives the mean value per particle. The actual volume of the particlesmay then be calculated as follows. First, the mean mass of a particle iscalculated. A sample of approximately 50 mg is taken and its preciseweight recorded to 0.1 mg. Then by optical microscopy the precise numberof particles in that sample is determined. The mean mass of one particlecan then be determined. The procedure is then repeated five times toobtain a mean value of this mean. Second, a fixed mass of particles(typically 50 g), is weighed out accurately, and the number of particleswithin this mass is calculated using the above mean mass value of oneparticle. Finally, the sample of particles is immersed in a liquid inwhich the particles are insoluble and, after agitation to remove trappedair, the amount of liquid displaced is measured. From this the meanactual volume of one particle can be calculated. The fissure index isadvantageously not less than 1.5, and is, for example, 2 or more.

[0026] 4. “Rugosity Coefficient”. The rugosity coefficient is used tomean the ratio of the perimeter of a particle outline to the perimeterof the ‘convex hull’. This measure has been used to express the lack ofsmoothness in the particle outline. The ‘convex hull’ is defined as aminimum enveloping boundary fitted to a particle outline that is nowhereconcave. (See “The Shape of Powder-Particle Outlines” A. E. Hawkins,Wiley.) The ‘rugosity coefficient’ may be calculated optically asfollows. A sample of particles should be identified from an electronmicrograph as identified above. For each particle the perimeter of theparticle outline and the associated perimeter of the ‘convex hull’ ismeasured to provide the rugosity coefficient. This should be repeatedfor at least ten particles to obtain a mean value. The mean rugositycoefficient is at least 1.25.

[0027] Carrier particles which have the above-mentioned capability ofretaining relatively large amounts of fine material without or with onlylittle segregation will generally comply with all of Methods 1 to 4above, but for the avoidance of doubt any carrier particles which complywith at least one of Methods 1 to 4 is deemed to be a fissured particle.

[0028] The carrier particles are advantageously in the form of anagglomerate consisting of a plurality of crystals fused to one another,the fastness of agglomeration being such that the carrier particles havesubstantially no tendency to disintegrate on expulsion from the inhalerdevice. In the case of crystalline sugars, such as lactose, suchstructures may be obtained in a wet granulation process, in whichcrystals within an agglomerate become fused to one another by solidbridges, the resultant structure having a complex shape of highirregularity and/or high fractal dimension, including a multiplicity ofclefts and valleys, which in some cases may be relatively deep. Eachagglomerate will generally contain at least three lactose primarycrystals of the characteristic tomahawk shape.

[0029] Such agglomerates are clearly distinguished from agglomerates ofthe kind which form in powder formulations by aggregation of particles,which do tend to disintegrate on expulsion from the inhaler.

[0030] Suitably shaped carrier particles also include dendriticspherulites of the type disclosed in U.S. Pat. No. 4,349,542 for use intable manufacture.

[0031] The carrier particles advantageously constitute at least 50%,preferably at least 60% and especially at least 70% by weight of theformulation, based on the total weight of the formulation.

[0032] The additive material, which is preferably on the surfaces of thecarrier particles, promotes the release of the active particles from thecarrier particles on actuation of the inhaler device. The formulationcontaining the additive material should, however, be such that theactive particles are not liable to be released form the carrierparticles before actuation of the inhaler device. The additive material,which it will be appreciated is of a different material from the carrierparticles, may be in the form of particles, the additive particles beingattached to the surfaces of the carrier particles.

[0033] In International Specification WO 96/23485 many examples aregiven of additive materials which are such that the active particles arenot liable to be released from the carrier particles before actuation ofthe inhaler device but are released during use of the inhaler device.“Actuation of the inhaler device” refers to the process during which adose of the powder is removed from its rest position in the inhalerdevice, usually by a patient inhaling. That step takes place after thepowder has been loaded into the inhaler device ready for use.

[0034] If it is desired to test whether or not the active particles of apowder are liable to be released from the carrier particles beforeactuation of the inhaler device a test can be carried out. A suitabletest is described in International Specification WO96/23485 (Example 12and 13). A powder whose post-vibration homogeneity measured as apercentage coefficient of variation, after being subjected to thedescribed test, is less than about 5% can be regarded as acceptable.

[0035] It is believed that additive material is attracted to and adheresto high energy sites on the surfaces of the carrier particles onintroduction of the active particles, many of the high energy sites arenow occupied, and the active particles therefore occupy the lower energysites on the surfaces of the carrier particles. That results in theeasier and more efficient release of the active particles in the airstream created on inhalation, thereby giving increased deposition of theactive particles in the lungs.

[0036] However, as indicated above, it has been found that the additionof more than a small amount of additive material can be disadvantageousbecause of the adverse effect on the ability to process the mix duringcommercial manufacture.

[0037] It is also advantageous for as little as possible of the additivematerial to reach the lungs on inhalation of the powder. Although theadditive material will most advantageously be one that is safe to inhaleinto the lungs, it is still preferred that only a very small proportion,if any, of the additive material reaches the lung, in particular thelower lung. The considerations that apply when selecting the additivematerial and other features of the powder are therefore different fromthe considerations when a third component is added to carrier and activematerial for certain other reasons, for example to improve absorption ofthe active material in the lung, in which case it would of course beadvantageous for as much as possible of the additive material in thepowder to reach the lung.

[0038] The optimum amount of additive material will depend on thechemical composition and other properties of the additive material. Ingeneral, the amount of additive will be not more than 50% by weight,based on the total weight of the formulations. However, it is thoughtthat for most additives the amount of additive material should be notmore than 10%, more advantageously not more than 5%, preferably not morethan 4% and for most materials will be not more than 2% or even not morethan 1% by weight or not more than 0.25% based on the total weight ofthe formulation. In general, the amount of additive material is at least0.01% by weight based on the total weight of the formulation.

[0039] Advantageously the additive material is an anti-adherent materialand will tend to decrease the cohesion between the anti-adherentmaterials and the carrier particles. In order to determine whether agiven material is an anti-adherent material, the test described inInternational Specification WO97/03649 (pages 6 and 7) using an“Aeroflow” apparatus may be used, anti-adherent materials being thoseadditive materials that result in a lowering of the mean time betweenavalanches of the powder, as compared with the powder in the absence ofthe additive material.

[0040] Advantageously the additive material is an anti-friction agent(glidant) and will give better flow of powder in the dry powder inhalerwhich will lead to a better dose reproducibility from the inhalerdevice.

[0041] Where reference is made to an anti-adherent material, or to ananti-friction agent, the reference is to include those materials whichwill tend to decrease the cohesion between the active particles and thecarrier particles, or which will tend to improve the flow of powder inthe inhaler, even though they may not usually be referred to asanti-adherent material or an anti-friction agent. For example, leucineis an anti-adherent material as herein defined and is generally thoughtof as an anti-adherent material but lecithin is also an anti-adherentmaterial as herein defined, even though it is not generally though of asbeing anti-adherent, because it will tend to decrease the cohesionbetween the active particles and the carrier particles. Advantageously,the additive material consists of physiologically acceptable material.As already indicated, it is preferable for only small amounts ofadditive material to reach the lower lung, and it is also highlypreferable for the additive material to be a material which may besafely inhaled into the lower lung where it may be absorbed into theblood stream. That is especially important where the additive materialis in the form of particles.

[0042] The additive material may include a combination of one or morematerials.

[0043] It will be appreciated that the chemical composition of theadditive material is of particular importance.

[0044] It will furthermore be appreciated that additive materials thatare naturally occurring animal or plant substances will offer certainadvantages.

[0045] Advantageously, the additive material includes one or morecompounds selected from amino acids and derivatives thereof, andpeptides and polypeptides having molecular weight from 0.25 to 100 Kda,and derivatives thereof. Amino acids, peptides or polypeptides and theirderivatives are both physiologically acceptable and give acceptablerelease of the active particles on inhalation.

[0046] It is particularly advantageous for the additive material tocomprise an amino acid. Amino acids have been found to give, whenpresent in low amounts in a powder as additive material, high respirablefraction of the active materials with little segregation of the powderand also with very little of the amino acid being transported into thelower lung. In respect of leucine, a preferred amino acid, it is foundthat, for example, for an average dose of powder only about 10 μg ofleucine would reach the lower lung. The additive material may compriseone or more of any of the following amino acids: leucine, isoleucine,lysine, valine, methionine, phenylalanine. The additive may be a salt ofa derivative of an amino acid, for example aspartame or acesulfame K.Preferably, the additive particles consist substantially of leucine,advantageously L-leucine. As indicated above, leucine has been found togive particularly efficient release of the active particles oninhalation. Whilst the L-form of an amino acid is used in Examplesdescribed below, the D- and DL-forms may also be used.

[0047] Additive materials which comprise one or more water solublesubstances offer certain advantages. This helps absorption of thesubstance by the body if the additive reaches the lower lung. Theadditive material may include dipolar ions, which may consist ofzwitterions.

[0048] Alternatively, the additive material may comprise particles of aphospholipid or a derivative thereof. Lecithin has been found to be agood material for the additive material.

[0049] The additive material may include or consist of one or moresurface active materials, in particular materials that are surfaceactive in the solid state, which may be water soluble, for examplelecithin, in particular soya lecithin, or substantially water insoluble,for example solid state fatty acids such as lauric acid, palmitic acid,stearic acid, erucic acid, behenic acid, or derivatives (such as estersand salts) thereof. Specific examples of such materials are: magnesiumstearate; sodium stearyl fumarate; sodium stearyl lactylate;phospatidylcholines, phosphatidylglycerols and other examples of naturaland synthetic lung surfactants; liposomal formulations; lauric acid andits salts, for example, sodium lauryl sulphate, magnesium laurylsulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugaresters in general.

[0050] Other possible additive materials include talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch.

[0051] The expression “additive material” as used herein does notinclude crystalline sugars. Whereas small particles of one or morecrystalline sugars may be present, and are indeed preferred to bepresent, as described below, formulations which contain smallcrystalline sugar particles will also contain a further substance whichis an additive material in the sense in which that expression is usedherein.

[0052] In the case of certain additive materials, it is important forthe additive material to be added in a small amount. For example,magnesium stearate is highly surface active and should therefore beadded in small amounts, for example, up to 2.5%, by weight based on theweight of the formulation with amounts of from 0.1 to 2% beingpreferred, for example, 0.5% to 1.7% especially 0.75 to 1.5% by weight.In some cases, it might be found advantageous to use smaller amounts ofmagnesium stearate, for example, from 0.02 to 0.6%, or 0.2 to 0.4% byweight. Phosphatidylcholines and phosphatidylgycerols on the other handare less active and can usefully be added in greater amounts. In respectof leucine, which is still less active, an addition of 2% by weightleucine based on the weight of the powder gives good results in respectof the respirable fraction of the active particles, low segregation andlow amount of leucine reaching the lower lung; it is explained in WO96/23485 that an addition of a greater amount does not improve theresults and in particular does not significantly improve the respirablefraction and therefore whilst even with 6% leucine a reasonable resultis obtained that is not preferred since it results in an increasedquantity of additive material being taken into the body and willadversely affect the processing properties of the mix. In the preferredformulations of the present invention using fissured carrier particles,however, it has been found that increased amounts of additive materialmay be used and give improved respirable fractions.

[0053] The additive material will often be added in particulate form butit may be added in liquid or solid form and for some materials,especially where it may not be easy to form particles of the materialand/or where those particles should be especially small, it may bepreferred to add the material in a liquid, for example as a suspensionor a solution or as a melt. Even then, however, the additive material ofthe finished powder may be in particulate form. An alternativepossibility, however, that is within the scope of the invention is touse an additive material which remains liquid even in the finalessentially particulate material which can still be described as a “drypowder”.

[0054] In some cases improved clinical benefits will be obtained wherethe additive material is not in the form of particles of material. Inparticular, the additive material is less likely to leave the surface ofthe carrier particle and be transported into the lower lung.

[0055] Where the additive material of the finished powder isparticulate, the nature of the particles may be significant. Theadditive particles may be non-spherical in shape. Advantageously, theadditive particles are plate-like particles. Alternatively, the additiveparticles may be angular for example prisms, or dendritic in shape.Additive particles which are non-spherical may be easier to remove fromthe surfaces of the carrier particles than spherical, non-angularparticles and plate-like particles may give improved surface interactionand glidant action between the carrier particles.

[0056] The surface area of the additive particles is also thought to beimportant. The surface area of the additive particles, as measured usinggas absorption techniques, is preferably at least 5 m²g⁻¹. In many casesit is found that additive material comprising small plate-like particlesis preferred.

[0057] Advantageously, at least 90% by weight of the additive particleshave an aerodynamic diameter less than 150 μm, more advantageously lessthan 100 μm, preferably less than 50 μm. Advantageously, the MMAD of theadditive particles is not more than 20 μm, preferably not more than 15μm, and more preferably not more than 10 μm. The additive particlespreferably have a mass median diameter less than the mass mediandiameter of the carrier particles and will usually have a mass mediandiameter of approximately between a tenth and a thousandth, for example,between a fiftieth and a five hundredth that of the carrier particles.The MMAD of the additive particles will generally be not less than 0.1μm, for example, not less than 1 μm.

[0058] The amount of additive material will depend upon the nature ofthe additive material, and will generally be at least 0.01% based on theweight of the carrier particles. In the case of additive materials thatdo not tend to segregate from the carrier particles, the additivematerial may be present in amounts of up to 50%, by weight, based on theweight of the carrier particles and additive. Advantageously, theadditive material may constitute up to one third of the combined weightof additive and carrier particles. In general, the amount of additivematerial will not exceed 10%, and preferably not exceed 5%, of thecombined weight of additive and carrier particles.

[0059] In the use of those additive materials which do have a tendencyto segregate, the amount of additive material will generally be lessthan 5%, for example not more than 3% by weight based on the combinedweight of additive material and carrier particles.

[0060] The active particles referred to throughout the specificationwill comprise an effective amount of at least one active agent that hastherapeutic activity when delivered into the lung. The active particlesadvantageously consist essentially of one or more therapeutically activeagents. Suitable therapeutically active agents may be drugs fortherapeutic and/or prophylactic use. Active agents which may be includedin the formulation include those products which are usually administeredorally by inhalation for the treatment of disease such a respiratorydisease, for example, β-agonists.

[0061] The active particles may comprise at least one β₂-agonist, forexample one or more compounds selected from terbutaline, salbutamol,salmeterol and formoterol. If desired, the active particles may comprisemore than one of those active agents, provided that they are compatiblewith one another under conditions of storage and use.

[0062] Preferably, the active particles are particles of salbutamolsulphate. References herein to any active agent are to be understood toinclude any physiologically acceptable derivative. In the case of theβ₂-agonists mentioned above, physiologically acceptable derivativesinclude especially salts, including sulphates.

[0063] The active particles may be particles of ipatropium bromide.

[0064] The active particles may include a steroid, which may bebeclometasone dipropionate or may be fluticasone. The active principlemay include a cromone which may be sodium cromoglycate or nedocromil.The active principle may include a leukotriene receptor antagonist.

[0065] The active particles may include a carbohydrate, for exampleheparin.

[0066] The active particles may advantageously comprise atherapeutically active agent for systemic use provided that that agentis capable of being absorbed into the circulatory system via the lungs.For example, the active particles may comprise peptides or polypeptidesor proteins such as DNase, leukotrienes or insulin (includingsubstituted insulins and pro-insulins), cyclosporin, interleukins,cytokines, anti-cytokines and cytokine receptors, vaccines (includinginfluenza, measles, ‘anti-narcotic’ antibodies, meningitis), growthhormone, leuprolide and related analogues, interferons, desmopressin,immunoglobulins, erythropoeitin, calcitonin and parathyroid hormone. Theformulation of the invention may in particular have application in theadministration of insulin to diabetic patients, thus avoiding thenormally invasive administration techniques used for that agent.

[0067] The formulations of the invention may advantageously be for usein pain relief. Non-opioid analgesic agents that may be included as painrelief agents are, for example, alprazolam, amitriptyline, aspirin,baclofen, benzodiazepines, bisphosphonates, caffeine, calcitonin,calcium-regulating agents, carbamazepine, clonidine, corticosteroids,dantrolene, dexamethasone, disodium pamidronate, ergotamine, flecainide,hydroxyzine, hyoscine, ibuprofen, ketamine, lignocaine, lorazepam,methotrimeprazine, methylprednisolone, mexiletine, mianserin, midazolam,NSAIDs, nimodipine, octreotide, paracetamol, phenothiazines,prednisolone, somatostatin. Suitable opioid analgesic agents are:alfentanil hydrochloride, alphaprodine hydrochloride, anileridine,bezitramide, buprenorphine hydrochloride, butorphanol tartrate,carfentanil citrate, ciramadol, codeine, dextromoramide,dextropropoxyphene, dezocine, diamorphine hydrochloride, dihydrocodeine,dipipanone hydrochloride, enadoline, eptazocine hydrobromide,ethoheptazine citrate, ethylmorphine hydrochloride, etorphinehydrochloride, fentanyl citrate, hydrocodone, hydromorphonehydrochloride, ketobemidone, levomethadone hydrochloride, levomethadylacetate, levorphanol tartrate, meptazinol hydrochloride, methadonehydrochloride, morphine, nalbuphine hydrochloride, nicomorphinehydrochloride, opium, hydrochlorides of mixed opium alkaloids,papaveretum, oxycodone, oxymorphone hydrochloride, pentamorphone,pentazocine, pethidine hydrochloride, phenazocine hydrobromide,phenoperidine hydrochloride, picenadol hydrochloride, piritramide,propiram furmarate, remifentanil hydrochloride, spiradoline mesylate,sufentanil citrate, tilidate hydrochloride, tonazocine mesylate,tramadol hydrochloride, trefentanil.

[0068] The technique could also be used for the local administration ofother agents for example for anti cancer activity, anti-virals,antibiotics, muscle relaxants, antidepressants, antiepileptics or thelocal delivery of vaccines to the respiratory tract.

[0069] The active particles advantageously have a mass medianaerodynamic diameter in the range of up to 15 μm, for example from 0.01to 15 μm, preferably from 0.1 to 10 μm, for example, from 1 to 8 μm.Most preferably, the mass median aerodynamic diameter of the activeparticles is not exceeding 5 μm. The active particles are present in aneffective amount, for example, at least 0.01% by weight, and may bepresent in an amount of up to 90% by weight based on the total weight ofcarrier particles, additive materials and active particles.Advantageously, the active particles are present in an amount notexceeding 60% by weight based on the total weight of carrier particles,additive particles and active particles.

[0070] It will be appreciated that the proportion of active agentpresent will be chosen according to the nature of the active agent. Inmany cases, it will be preferred for the active agent to constitute nomore than 10%, more preferably no more than 5%, and especially no morethan 2% by weight based on the total weight of carrier particles,additive particles and active particles.

[0071] The formulation may further comprise fine particles of anexcipient material, that is to say, particles of aerodynamic diameternot more than 50 μm, of a substantially inert pharmacologicallyacceptable material. The excipient material may be any substantiallyinert material that is suitable for use as an excipient in an inhalableformulation. The excipient material preferably comprises one or morecrystalline sugars, for example, dextrose and/or lactose. Mostpreferably the excipient material consists essentially of lactose.

[0072] Advantageously, the fine excipient particles are of the samematerial as the carrier particles. It is especially preferred for thecarrier particles and the fine excipient particles to be of lactose.

[0073] Advantageously, at least 90% by weight of the fine excipientparticles have an aerodynamic diameter of not more than 40 μm. The fineexcipient particles advantageously have an MMAD of not more than 20 μm,preferably not more than 15 μm, more preferably not more than 10 μm, andespecially not more than 8 μm. The MMAD of the fine excipient particleswill generally be not less than 0.1 μm, for example not less than 1 μm.Advantageously the fine excipient particles are present in an amount ofup to 50%, for example from 0.1 to 20%, and preferably from 1 to 15%, byweight based on the total weight of the formulation.

[0074] Where fine excipient particles are present, they may be presentin an amount of up to 99% by weight of the total weight of fineexcipient particles and additive material. Advantageously, fineexcipient particles are present in an amount of at least 30%, preferablyat least 50% and especially at least 90% by weight, based on the totalweight of fine excipient particles and additive material. The fineexcipient particles and additive material, advantageously constitutefrom 5%, or from 10% to two thirds by weight of the total weight of fineexcipient particles, additive material and carrier particles.

[0075] Where, as is preferred, the carrier particles and the fineexcipient particles are of the same compound, for example, lactose, itmay be found convenient to consider all the particles of that compoundhaving an aerodynamic diameter of less than 50 μm to be fine excipientparticles, whilst particles of aerodynamic diameter of 50 μm or more areregarded as carrier particles.

[0076] The advantageous flow properties of formulations of the inventionmay be demonstrated, for example, using a Flodex Tester, which candetermine a flowability index over a scale of 4 to 40 mm, correspondingto a minimum orifice diameter through which smooth flow of theformulation occurs in the Tester. The flowability index, when someasured, of formulations of the invention containing fissured lactosewill generally be below 12 mm, even where fine particle contents (thatis, particles of aerodynamic diameter less than 50 μm or preferably lessthan 20 μm) exceed 10% by weight of the formulation.

[0077] The invention provides a formulation for use in a dry powderinhaler, comprising more than 5%, preferably more than 10% by weight,based on the total weight of the formulation, of particles ofaerodynamic diameter less than 20 μm, the formulation having aflowability index of 12 mm or less. The term “flowability index” as usedherein refers to flowability index values as measured using a FlodexTester.

[0078] In addition to the carrier particles, active particles and fineexcipient particles, the formulation may comprise one or more furtheradditives suitable for use in inhaler formulations, for example,flavourings, lubricants, and flow improvers. Where such furtheradditives are present, they will generally not exceed 10% by weight ofthe total weight of the formulation.

[0079] The formulations of the invention may be made by combining thecomponents in any suitable manner. In a preferred method, however, theformulations are made by mixing the additive and fine excipientparticles in a high energy mixing step, mixing the composite particlesso obtained with the carrier particles, and adding to the mixture soobtained the at least one active ingredient. In another advantageousmethod, additive particles and excipient particles are co-micronised soas to significantly reduce their particle size, the co-micronisedparticles are mixed with the carrier particles, and the at least oneactive ingredient is added to the mixture so obtained. Suitable mixersfor carrying out a high energy mixing step in the context of suchformulations are high shear mixers. Such mixers are known to thoseskilled in the art, and include, for example, the Cyclomix and theMechano-Fusion mixers manufactured by Hosokawa Micron. It will beappreciated by those skilled in the art that other suitable apparatusfor use in a high energy mixing step will include, for example, ballmills and jet mills, provided that the equipment and conditions are soarranged to effect the desired high energy mixing.

[0080] The formulation may be a powder formulation for use in a drypowder inhaler. The formulation may be suitable for use in a pressurisedmetered dose inhaler.

[0081] One embodiment of the invention will now be described in detailwith reference to the accompanying illustrations in which:

[0082]FIG. 1 is a scanning electron micrograph (SEM) of a relativelyhighly fissured lactose particle;

[0083]FIG. 2 is an SEM at lower magnification than FIG. 1 showing anumber of lactose particles;

[0084]FIG. 3 is an SEM of a lactose carrier particle loaded with leucineand salbutamol sulphate; and

[0085]FIG. 4 is an SEM of a formulation containing conventional lactosecarrier particles and fine excipient particles.

[0086] With reference to FIG. 1, it may be seen that the lactose carrierparticle consists of a number of individual lactose crystals which arefused to one another. The crystals define between them at the surface ofthe particle a multiplicity of relatively deep fissures or crevices.Such particles are known and have previously been regarded as suitablefor use in tablet manufacture. Surprisingly, it has been found thatcarrier particles such as that shown in FIG. 1 are able to enhance thefine particle fraction of an active substance in the presence ofadditive. The active substance, together with the fine excipient, tendbecause of their small particle size and consequent high surface energyto adhere to the carrier particles. Adhesion occurs predominantly withinthe fissures and crevices. Due to the optimum width, depth and shape ofthe fissures, the resultant loaded carrier particles have good stabilityagainst deagglomeration within the inhaler device and yet permiteffective dispersion of the active particles and fine excipient onexpulsion from the device after actuation.

[0087]FIG. 2 shows a group of carrier particles similar to that of FIG.1.

[0088] Referring to FIGS. 3 and 4, the lactose carrier particle of FIG.3 holds the fine material, consisting of leucine as additive materialand salbutamol sulphate as active material, within the fissures of itsagglomerated structure to form a relatively cohesive structure, whilstin the conventional formulation of FIG. 4 much of the fine material isnot adhered to the lactose carrier particles. The conventional carrierparticles are typically crystals which have the characteristic tomahawkshape of lactose crystals. They may also be amorphous in shape, butrarely consist of more than two fused crystals. Thus the conventionalcarrier particles are substantially without the clefts and valleys ofthe fissured particles used in accordance with the present invention.

[0089] References herein to a “diameter” in relation to carrierparticles means the diameter determined using laser diffraction, forexample, using a Malvern Mastersizer, and references herein to a “massmedian diameter” in relation to carrier particles is to be interpretedaccordingly.

[0090] It may be found convenient to determine the diameters ofparticles in a formulation according to the invention by dispersing theparticles in a liquid that does not dissolve any of the componentparticles, sonicating to ensure complete dispersion, and analysing thedispersion by means of laser diffraction, for example using a MalvernMastersizer. That method will be suitable where separate analysis offine particles of different materials is unnecessary.

[0091] In practice, it may be desired to examine a larger particle sizefraction separately from a smaller size fraction. In that case, an airjet sieve may be used to effect separation. A mesh corresponding to thedesired diameter at which the separation is to be effected is then usedin the air jet sieve. A mesh corresponding to a diameter of 50 μm maythus be used for separation, larger particles being retained by thesieve whilst smaller particles pass through to be collected on a filter.That enables different techniques to be applied to analysis of thelarger particles (≧50 μm) and the smaller particles (<50 μm) if desired.

[0092] In the case of particles of the size of the carrier particlesused in accordance with the invention, the diameter as measured usinglaser diffraction approximates the aerodynamic diameter. If preferred,therefore, the aerodynamic diameters of the carrier particles may bedetermined and the mass median aerodynamic diameter (MMAD) calculatedtherefrom.

[0093] MMADs referred to herein in relation to additive materials, fineexcipient particles and active particles may be measured using anysuitable technique, for example, using an impactor such as a cascadeimpactor, and analysing the size fractions so obtained, for exampleusing HPLC.

[0094] Alternatively, respective samples of the formulation may each betreated with a solvent that is known to disolve one or more, but notall, of the ingredients and examining the undisolved particles by anysuitable method, for example, laser diffraction.

[0095] The following Examples illustrate the invention.

EXAMPLE 1

[0096] 20 g of Microfine lactose (Burculo—MMAD about 8 μm) and 0.4 g ofL-leucine (Ajinomoto) were combined and placed in a stainless steel ballmill, filled with stainless steel balls of varying diameter toapproximately 50% of the mill volume. The mill was rotated atapproximately 60 RPM for about 120 minutes. The milled material (MMADabout 5 μm) was then recovered from the mill and from the surface of theballs, and is referred to below as the fines.

[0097] 8 g of sieved Prismalac lactose was weighed into a glass vessel.Prismalac (trade mark) lactose is sold in the UK by Meggle for use intablet manufacture. The lactose, as purchased, had been sieved on astack of sieves in order to recover the sieve fraction passing through a600 μm mesh sieve, but not passing through a 355 μm mesh sieve. Thatfraction is referred to below as 355-600 Prismalac and has a mean tappeddensity of 0.49 g/cm³ and a bulk density as measured by mercuryintrusion porosimetry of 0.47 g/cm³.

[0098] 1 g of the fines obtained as described above, and 1 g ofmicronised salbutamol sulphate (MMAD˜2 μm) was added to the 355-600Prismalac in the glass vessel. The glass vessel was sealed and thevessel located in a “Turbula” tumbling blender. The vessel and contentswere tumbled for approximately 30 minutes at a speed of 42 RPM.

[0099] The formulation so obtained was loaded into size 3 gelatincapsules at 20 mg per capsule. The loaded capsules were rested for aperiod of 24 hours. Three capsules were then fired sequentially into aTwin Stage Impinger from a Cyclohaler at a flow rate of 60 litres perminutes, with a modified stage 1 jet of 12.5 mm internal diameter, whichwas estimated to produce a cut-off diameter of 5.4 μm. The operation ofthe Twin Stage Impinger is described in WO95/11666. Modification of aconventional Twin Stage Impinger, including the use of modified stage 1jets, is described by Halworth and Westmoreland (J. Pharm. Pharmacol.1987, 39:966-972). TABLE 1 Example 1 Comparison 1 Comparison 2 355-600Prismalac 8 g 80% 8 g   4 g lactose Salbutamol sulphate 1 g 10% 1 g 0.5g Microfine lactose 0.9804 g 9.804% — 0.5 g Leucine 0.0196 g 0.196% —Fine particle 50% 10% 40% fraction

[0100] The composition of the formulation is summarised in Table 1above.

[0101] As shown in Table 1, the fine particle fraction is improved inthe presence of added fine lactose (Comparison 2) as compared with aformulation which contains no added fine lactose (Comparison 1). Thebest performance is obtained from the formulation according to theinvention, containing leucine as well as fine lactose. On omission ofthe Prismalac from the ingredients of Example 1, the formulation wasfound to have very poor flow properties, preventing reliable andreproducible metering. As a result, the fine particle fraction was foundto be very variable.

EXAMPLE 2

[0102] Example 1 was repeated using micronised budesonide (MMAD 2 μm) inplace of salbutamol sulphate, and magnesium stearate in place ofleucine. The results are summarised in Table 2, which also indicates theamounts of each ingredient. TABLE 2 355-600 Prismalac   4 g 80% lactoseBudesonide  0.5 g 10% Microfine lactose 0.45 g  9% Magnesium stearate0.05 g  1% Fine particle 40% fraction

EXAMPLE 3

[0103] Example 1 was repeated using Prismalac lactose which had beensieved, the sieve fractions of 212 to 355 μm (with mean tapped density0.65 g/cm³ and a bulk density as measured by mercury instrusionporosimetry of 0.57 g/cm³) being recovered and used instead of the355-600 Prismalac lactose used in Example 1. Once again, a fine particlefraction of about 50% was obtained.

EXAMPLE 4

[0104] Example 1 was repeated replacing the leucine by one of thefollowing: lecithin, stearylamine, magnesium stearate, and sodiumstearyl fumarate.

[0105] The results are summarised in Table 3. TABLE 3 Additive Fineparticle fraction Lecithin 50% Stearylamine 50% Purified phosphatidylcholines 35% Sodium stearyl fumarate 40%

EXAMPLE 5

[0106] Micronised salbutamol sulphate was mixed with 5% by weight ofsublimed L-leucine in a blender. The mixture so obtained was thentumbled in the ratio of 1:6 with Prismalac (355 to 600 μm fraction) for15 minutes. The fine particle fraction, determined using a Twin StageImpinger modified as described in Example 1, was 65%.

EXAMPLE 6

[0107] 95 g of Microfine lactose (Borculo) was placed in a ceramicmilling vessel (manufactured by the Pascall Engineering Company). 5 g ofadditive material (L-leucine) and the ceramic milling balls were added.The ball mill was tumbled at 60 rpm for 5 hours. The powder wasrecovered by sieving to remove the milling balls.

[0108] 0.9 g of the composite excipient particles so obtained containing5% l-leucine in Microfine lactose was blended with 0.6 g of budesonideby hand in a mortar. This blending could also be performed, for example,in a high shear blender, or in a ball mill or in a centrifugal mill. 20parts by weight of this powder were blended with 80 parts by weight of acoarse carrier lactose (sieve-fractionated Prismalac—355 to 600 μmfraction) by tumbling. The powder was fired from a Cyclohaler at a flowrate of 60 l/minute in a multi-stage liquid impinger. The fine particlefraction (<approx. 5 μm) was 45%.

EXAMPLE 7

[0109] 98 g of Microfine (MMAD approximately 8 μm) lactose (manufacturedby Borculo) was placed in a stainless steel milling vessel. 300 g ofstainless steel milling balls varying from 10 to 3 mm diameter wereadded. 2 g of lecithin was added and the vessel was located in a RetschS100 Centrifugal Mill. The powder was milled for 30 minutes at 580 rpmand was then sieved to remove the milling balls.

[0110] 1 g of salbutamol sulphate was added to 1 g of the compositeexcipient particles so obtained containing 2% lecithin, and to 8 g ofsieve-fractionated Prismalac lactose (355 to 600 μm fraction). Themixture was tumbled for 30 minutes at 42 rpm. The resulting powder wasfired from a Cyclohaler at a flow rate of 60 litres per minute into atwin-stage impinger, giving a fine particle fraction (<approx. 5 μm) ofabout 44%. A similar example with a 2% leucine precursor gave a fineparticle fraction (<approx. 5 μm) of 52%.

[0111] Other additive materials that may be used instead of lecithin toform composite excipient particles as described above are: magnesiumstearate, calcium stearate, sodium stearate, lithium stearate, stearicacid, stearylamine, soya lecithin, sodium stearyl fumarate, l-leucine,l-isoleucine, oleic acid, starch, diphosphatidyl choline, behenic acid,glyceryl behenate, and sodium benzoate. Pharmaceutically acceptablefatty acids and derivatives, waxes and oils may also be used.

EXAMPLE 8

[0112] 10 g of Microfine lactose (Borculo) was combined with 1 g ofmagnesium stearate and 10 cm³ cyclohexane. 50 g of 5 mm balls were addedand the mixture was milled for 90 minutes. The powder was recovered byleaving the paste in a fume hood overnight to evaporate the cyclohexaneand then ball milling for 1 minute.

[0113] 0.5 g of salbutamol sulphate was added to 0.5 g of the compositeexcipient particles so obtained containing magnesium stearate, and to 4g of sieve-fractionated Prismalac lactose (355-600 μm fraction). Thiswas tumbled for 30 minutes at 62 rpm. The resulting powder was firedfrom a Cyclohaler at a flow rate of 60 litres per minute into atwin-stage impinger, giving a fine particle fraction (<approx. 5 μm) of57%. The experiment was repeated using composite excipient particlescontaining 20% magnesium stearate and similar results were obtained.

EXAMPLE 9

[0114] 10 g of Microfine lactose (Borculo) was combined with 1 g ofleucine and 10 cm³ cyclohexane. 50 g of 5 mm balls were added and themixture was milled for 90 minutes. The powder was recovered by leavingthe paste in a fume hood overnight to evaporate the cyclohexane and thenball milling for 1 minute.

[0115] 0.5 g of salbutamol sulphate, 0.25 g of composite excipientparticles made as described in Example 8 containing magnesium stearate,0.25 g of composite excipient particles made as described abovecontaining leucine, and 4 g of sieve-fractionated Prismalac (355-600 μmfraction) were all combined. The mixture was tumbled for 30 minutes at62 rpm. The resulting powder was fired from a Cyclohaler at a flow rateof 60 litres per minute into a twin-stage impinger, giving a fineparticle fraction (<approx. 5 μm) of 65%.

EXAMPLE 10

[0116] 10 g of Microfine lactose (Borculo) was combined with 1 g oflecithin and 10 cm³ cyclohexane. 50 g of 5 mm balls were added and themixture was milled for 90 minutes. The powder was recovered by leavingthe paste in a fume hood overnight to evaporate the cyclohexane and thenball milling for 1 minute.

[0117] 0.5 g of salbutamol sulphate was added to 0.25 g of the compositeexcipient particles so obtained containing lecithin, 0.25 g of compositeexcipient particles made as described in Example 9 containing leucine,and 4 g of sieve-fractionated Prismalac lactose (355-600 μm fraction).The mixture was tumbled for 30 minutes at 62 rpm. The resulting powderwas fired from a Cyclohaler at a flow rate of 60 litres per minute intoa twin-stage impinger, giving a fine particle fraction (<approx. 5 μm)of 68%.

EXAMPLE 11

[0118] 95 g Sorbolac 400 (Meggle) were combined with 5 g of magnesiumstearate and 50 ml dichloromethane and milled in a Retsch S100centrifugal mill with 620 g of 5 mm stainless steel balls in a stainlesssteel vessel for 90 minutes at 500 rpm. The powder was recovered afterevaporation of the dichloromethane by briefly milling (1 minute) andsubsequent sieving. 10 g of the composite excipient/additive particlesso obtained were added to 89.5 g of sieve fractionated Prismalac lactose(355-600 μm fraction). The mixture was tumbled for 30 minutes at 60 rpm,then 0.5 g budesonide was added and tumbling continued for a further 30minutes at 60 rpm. The powder was fired from a Cyclohaler at 60 l/minuteinto a Twin-Stage Impinger, and gave a fine particle fraction (<approx.5 μm) of about 80%.

EXAMPLE 12

[0119] (a) A pre-blend was made by milling an additive material andmicrofine lactose (<20 micron) together in a ball mill. Then 1 g of thepre-blend, 1 g of salbutamol sulphate and 8 g of coarse lactose(Prismalac 355-600 μm fraction) were mixed together in a glass vessel ina Turbula mixer at 42 rpm to create the final formulation. Size 2capsules were filled with 20 mg of the formulation. For each test, 3capsules were fired into a ‘rapid TSI’ from a cyclohaler giving a totaldelivered dose of 6 mg of salbultamol sulphate per test. The additivematerial was selected from lithium stearate, calcium stearate, magnesiumstearate, sodium stearate, sodium stearyl fumarate, leucine, lecithinand stearylamine.

[0120] (b) The method of (a) above was repeated using leucine, exceptthat the pre-blend was mixed with the coarse lactose in a glass vesselshaken by hand.

[0121] The “rapid TSI” is a modified methodology based on a conventionalTSI. In the rapid TSI the second stage of the impinger is replaced by aglass fibre filter (Gelman A/E, 76 mm). This enables the fine particlefraction of the formulation (i.e. particles with an MMAD<5 μm) to becollected on a filter for analysis. Analysis was conducted by sonicatingthe filter in a 0.06M NaOH solution and analysed at 295 nm on a UVspectrophotomer (Spectronic 601). The fine particle fraction correspondssubstantially to the respirable fraction of the formulation.

[0122] Further details of the formulations and the % fine particlefraction estimated using the “rapid TSI” method described above aregiven in Table 4 below.

[0123] Segregation has not been observed in the above formulations, eventhose comprising 10 and 20% magnesium stearate (i.e. up to 2% in thefinal composition).

[0124] The above processes have been applied to a variety of activematerials. When the active material is a protein, the milling may bepreceded by lyophilisation (freeze drying) of the protein either pure orin combination with an additive material and/or a polymeric stabiliser.The freeze drying may make the protein more brittle and more easilymilled. The milling may need to be conducted under cryogenic (cold)conditions to increase the brittleness of the material. TABLE 4 Additive% AM in % AM in Mass (mg) Estimated Pre-blend Material (“AM”) pre-blendformulation SaS04 % FPF mill method Lithium St 2 0.2 2.549 42 30 mins2.763 46 Calcium St 2 0.2 2.721 45  1 hr 2.633 44 Magnesium St 2 0.22.108 35  1 hr 2.336 39 Sodium St 2 0.2 3.218 54 30 mins 3.153 53 Sodiumstearyl 2 0.2 2.261 38 30 mins Fumarate 2.113 35 Leucine 2 0.2 2.429 40 2 hrs 2.066 34 Leucine 2 0.2 2.136 36  2 hrs [12 (b)] 2.600 43 Leucine5 0.5 2.782 46 30 mins 3.000 50 Leucine 5 0.5 2.772 46 2.921 49  5 hrsMagnesium St 5 0.5 2.438 41 30 mins 2.721 45 Lecithin 2 0.2 3.014 50 30mins 2.884 48 Stearylamine 2 0.2 2.847 47 30 mins 3.037 51

EXAMPLE 13

[0125] Determination of the suitable amount of magnesium stearate to beadded in the formulation.

[0126] Samples of pre-blends were prepared by co-milling in a ballmilling apparatus for 2 hours α-lactose monohydrate SorboLac 400 (Megglemicrotose) with a starting particle size below 30μ(d(v, 0.5) of about 10μm) and magnesium stearate with a starting particle size of 3 to 35 μm(d(v, 0.5) of about 10 μm) in the ratio 98:2, 95:5 and 90:10% by weight(blends A).

[0127] 85% by weight of α-lactose monohydrate CapsuLac (212-355 μm) wasplaced in a 240 ml stainless steel container, then 15% by weight of arespective blend A was added. The blend was mixed in a Turbula mixer for2 hours at 42 rpm (blend B). Micronised formoterol fumarate was added tothe blend B and mixed in a Turbula mixer for 10 mins at 42 rpm to obtaina ratio of 12 μg of active to 20 mg of carrier. The final formulation(hard pellet formulation) was left to stand for 10 mins then transferredto an amber glass jar.

[0128] The amount of magnesium stearate in the final formulations turnsout to be 0.3, 0.75 and 1.5% by weight, respectively. The uniformity ofdistribution of active ingredient and the in-vitro aerosol performancewere determined as follows:

[0129] a) The uniformity of distribution of the active ingredient wasevaluated by withdrawing 10 samples, each equivalent to about a singledose, from different parts of the blend. The amount of active ingredientof each sample was determined by High-Performance Liquid Chromatography(HPLC).

[0130] b) Determination of the aerosol performances.

[0131] An amount of powder for inhalation was loaded in a multidose drypowder inhaler (Pulvinal®—Chiesi Pharmaceutical SpA, Italy).

[0132] The evaluation of the aerosol performances was performed by usinga modified Twin Stage Impinger apparatus, TSI (Apparatus of type A forthe aerodynamic evaluation of fine particles described in FU IX, 4°supplement 1996). The equipment consists of two different glasselements, mutually connected to form two chambers capable of separatingthe powder for inhalation depending on its aerodynamic size; thechambers are referred to as higher (stage 1) and lower (stage 2)separation chambers, respectively. A rubber adaptor secures theconnection with the inhaler containing the powder. The apparatus isconnected to a vacuum pump which produces an air flow through theseparation chambers and the connected inhaler. Upon actuation of thepump, the air flow carries the particles of the powder mixture, causingthem to deposit in the two chambers depending on their aerodynamicdiameter. The apparatus used were modified in the Stage 1 Jet in orderto obtained an aerodynamic diameter limit value, dae, of 5 μm at an airflow of 30 l/min, that is considered the relevant flow rate forPulvinal® device. Particles with higher dae deposit in Stage 1 andparticles with lower dae in Stage 2. In both stages, a minimum volume ofsolvent is used (30 ml in Stage 2 and 7 ml in Stage 1) to preventparticles from adhering to the walls of the apparatus and to promote therecovery thereof.

[0133] The determination of the aerosol performances of the mixtureobtained according to the preparation process a) was carried out withthe TSI applying an air flow rate of 30 l/min for 8 seconds.

[0134] After nebulization of 10 doses, the Twin Stage Impinger wasdisassembled and the amounts of drug deposited in the two separationchambers were recovered by washing with a solvent mixture, then dilutedto a volume of 100 and 50 ml in two volumetric flasks, one for Stage 1and one for Stage 2, respectively. The amounts of active ingredientcollected in the two volumetric flasks were then determined byHigh-Performance Liquid Chromatography (HPLC). The following parameters,were calculated: i) the shot weight expressed as mean and relativestandard deviation (RSD) ii) the fine particle dose (FPD) which is theamount of drug found in stage 2 of TSI; iii) the emitted dose which isthe amount of drug delivered from the device recovered in stage 1+stage2; iv) the fine particle fraction (FPF) which is the percentage of theemitted dose reaching the stage 2 of TSI. TABLE 5 Uniformity ofdistribution and in-vitro aerosol performances Mg stearate Mg stearateMg stearate 0.3% 0.75% 1.5% Content uniformity Mean (μg) 11.84 — — RSD(%) 1.83 — — Shot weight Mean (mg) 20.8 24.7 23.0 4.28 49.9 RSD (%) 6.96.5 2.4 Emitted dose (μg) 8.57 10.1 11.1 FPD (μg) 4.28 3.5 3.6 FPF (%)49.9 35 32

[0135] In all cases, good performances in terms of fine particle doseare obtained, in particular with 0.3% by weight of magnesium stearate inthe final formulation.

EXAMPLE 14 Effect of the Addition of Magnesium Stearate By Simple Mixing

[0136] Formulation A—α-Lactose monohydrate Pharmatose 325M (30-100 μm)and magnesium stearate in the ratio 99.75:0.25% by weight were blendedin a Turbula mixer for 2 hours at 42 rpm. The blend was mixed withformoterol fumarate in a Turbula mixer for 30 mins at 42 rpm to obtain aratio of 12 μg of active to 25 mg of carrier.

[0137] Formulation B—as reported above but α-Lactose monohydrateSpheroLac 100 (90-150 μm) was used instead of Pharmatose 325M.

[0138] Formulation C—α-Lactose monohydrate PrismaLac 40 (with a particlesize below 355 μm) and micronised lactose with a particle size below 5μm in the ratio 40:60% by weight were mixed in a Turbula mixer for 60mins at 42 rpm 99.75% by weight of the resulting blend and 0.25% byweight of magnesium stearate were mixed in a Turbula mixer for 60 minsat 42 rpm. The resulting blend was finally mixed with formoterolfumarate in a Turbula mixer for 30 mins at 42 rpm to obtain a ratio of12 μg of active to 15 mg of carrier.

[0139] Formulation D—Sorbolac 400 with a particle size below 30 μm (d(v,0.5) of about 10 μm) and magnesium stearate in the ratio 98:2% by weightwere mixed in a high shear mixer for 120 mins (blend A). 85% by weightα-lactose monohydrate CapsuLac (212-355 μm) and 15% by weight of blend Awere mixed in Turbula for 2 hours at 42 rpm (blend B); the amount ofmagnesium stearate in the final formulation is 0.3% by weight.Micronised formoterol fumarate was placed on the top of blend B andmixed in a Turbula mixer for 10 mins at 42 rpm to obtain a ratio of 12μg of active to 20 mg of carrier.

[0140] Formulation E—Micronized lactose with a particle size below 10 μm(d(v, 0.5) of about 3 μm) and magnesium stearate in the ratio 98:2% byweight were mixed in a Sigma Blade mixer for 60 mins (blend A). 85% byweight of α-lactose monohydrate CapsuLac (212-355 μm) and 15% by weightof blend A were mixed in Turbula for 2 hours at 42 rpm (blend B); theamount of magnesium stearate in the final formulation is 0.3% by weight.Micronised formoterol fumarate was placed on the top of blend B andmixed in a Turbula mixer for 10 mins at 42 rpm to obtain a ratio of 12μg of active to 20 mg of carrier.

[0141] The results in terms of uniformity of distribution of activeingredient and in-vitro aerosol performances were determined asdescribed in Example 13 and are reported in Table 6. TABLE 6 Uniformityof distribution of active ingredient and in-vitro aerosol performancesFormulations Formulations Formulations Formulations Formulations A B C DE Content uniformity Mean (μg) 7.96 10.50 9.10 10.68 11.32 RSD (%) 2.168.30 24.90 2.80 3.0 Shot weight Mean (mg) 24.10 26.50 12.50 22.07 21.87RSD (%) 34.60 8.20 15.30 2.50 4.0 Emitted dose (μg) 6.10 7.60 9.60 8.609.93 FPD (μg) 0.60 0.90 1.60 3.38 4.80 FPF (%) 9.8 11.8 16.7 39.3 48.37

[0142] Formulations where magnesium stearate is added by a high energymixing to a small amount of fine lactose (blend A of the formulations Dand E), and combined with a 212-355 μm coarse lactose fraction, show asignificant increase in performance. In addition, the particle size ofthe fine lactose used has a significant effect on the deaggregationproperties of the final formulation; in fact, formulation E preparedusing a micronized lactose shows a significant improved performancecompared with formulation D.

EXAMPLE 15 Effect of the Amount of Micronized Pre-blend in the FinalFormulation

[0143] α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with astarting particle size of 50 to 400 μm (d(v, 0.5) of about 170 μm andmagnesium stearate with a starting particle size of 3 to 35 μm (d(v,0.5) of about 10 μm) in the ratio 98:2% by weight were co-milled in ajet mill apparatus (blend A)Different ratios of α-lactose monohydrateCapsulac (212-355 μm) and blend A were placed in a stainless steelcontainer and mixed in a Turbula mixer for four hours at 32 rpm (blendsB).

[0144] Micronised formoterol fumarate was placed on the top of blends Band mixed in a Turbula mixer for 30 mins at 32 rpm to obtain a ratio of12 μg of active to 20 mg total mixture. The amount of magnesium stearatein the final formulation ranges between 0.05 and 0.6% by weight.

[0145] The results in terms of uniformity of distribution of activeingredient and in-vitro aerosol performances were determined as inExample 13 and are reported in Table 7. TABLE 7 Uniformity ofdistribution of active ingredient and in-vivo aerosol performance RatioRatio Ratio Ratio Ratio Ratio 97.5:2.5 95:5 92.5:7.5 90:10 80:20 70:30Content uniformity Mean (g) 11.29 12.25 11.53 11.93 11.96 12.00 RSD (%)3.8 5.7 1.5 2.5 2.0 2.0 Shot weight Mean (mg) 19.27 20.26 20.38 21.0522.39 22.48 RSD (%) 4.7 3.3 3.2 4.3 3.5 3.7 Emitted dose (μg) 10.58 9.2010.65 9.18 9.63 9.88 FPD (μg) 4.18 5.10 6.78 5.9 5.33 5.28 FPF (%) 39.455.4 63.6 64.3 55.3 53.4

[0146] The results indicate that the performances of all theformulations are good.

EXAMPLE 16

[0147] 10 g of the composite excipient particles containing 5% magnesiumstearate obtained in accordance with Example 11 were mixed with 89.5 gcoarse lactose (Prismalac; 355-600 μm fraction) in a Turbula mixer for30 minutes. 0.5 g micronised dihydroergotamine mesylate was added andmixing continued in the Turbula for a further 30 minutes. The powder wasfired from a Cyclohaler into a Multi-Stage Liquid Impinger (Apparatus C,European Pharmacopoeia, Method 5.2.9.18, Supplement 2000), and gave afine particle fraction (<approx. 5 82 m) of about 60%.

EXAMPLE 17

[0148] Composite excipient particles were manufactured by milling 95 gfine lactose (Sorbolac 400—Meggle) with 5 g magnesium stearate and 50 mldichloromethane in a Retsch S100 centrifugal mill with 620 g of 5 mmstainless steel balls in a stainless steel vessel for 90 minutes at 500rpm. The powder was recovered after evaporation of the dichloromethaneby briefly milling (1 minute) and subsequent sieving. 10 g of thecomposite excipient/additive particles so obtained were added to 89.5 gof sieve fractionated Prismalac lactose (355-600 μm fraction). Themixture was tumbled in a Turbula mixer for 30 minutes at 60 rpm, then0.5 g fentanyl citrate was added and tumbling continued for a further 30minutes at 60 rpm. The powder so obtained was fired from a Cyclohaler at60 l/min into a Twin-Stage Impinger, and gave a fine particle fraction(<approx. 5 μm) of about 50%.

EXAMPLE 18

[0149] Various formulations, each combining 89.5 g, 10 g compositeexcipient particles and 0.5 g budesonide were made according to themethod of Example 11.

[0150] Their flowabilities were then measured using a FLODEX (trademark) tester, made by Hanson Research. The FLODEX provides an index,over a scale of 4 to 40 mm, of flowability of powders. Analysis wasconducted by placing 50 g of formulation into the holding chamber of theFLODEX via a funnel, allowing the formulation to stand for 1 minute, andthen releasing the trap door of the FLODEX to open an orifice at thebase of the holding chamber. Orifice diameters of 4 to 34 mm were usedto measure the index of flowability. The flowability of a givenformulation is determined as the smallest orifice diameter through whichflowing of the formulation is smooth.

[0151] The results are shown in Table 8.

[0152] Comparison data is given for a formulation made by mixing for 30minutes in a Turbula mixer 45 g Pharmatose 325M lactose (a lactose usedin certain conventional formulations) and 5 g microfine lactose. TABLE 8Carrier particles Composite particles Flowability Prismalac 355-600Leucine:Sorbolac400 1:9 <4 mm Prismalac 355-600 Lecithin:Sorbolac400 1:9<4 mm Prismalac 355-600 Magnesium stearate:Sorbolac400 <4 mm 1:19Prismalac 355-600 Magnesium stearate:microfine lactose <4 mm 1:19Pharmatose 325M Microfine lactose <34 mm 

[0153] The results in Table 8 illustrate the excellent flowability ofthe formulations according to the invention.

COMPARISON EXAMPLE 1

[0154] 99.5 g of sieve-fractionated Prismalac (355-600 μm fraction) wastumbled with 0.5 g budesonide for 30 minutes at 60 rpm. The powder,fired from a Cyclohaler at 90 litres per minute into a Multi-StageLiquid Impinger gave a fine particle fraction (<approx. 5 μm) of about30%.

1. A formulation for use in an inhaler device, comprising carrierparticles having a diameter of at least 50 μm and a mass median diameterof at least 175 μm; active particles; and additive material which isable to promote release of the active particles from the carrierparticles on actuation of the inhaler device.
 2. A formulation accordingto claim 1, in which the mass median diameter of the carrier particlesis at least 200 μm.
 3. A formulation according to claim 1 or claim 2, inwhich the carrier particles are of a crystalline sugar.
 4. A formulationaccording to claim 3, in which the carrier particles are of dextrose orlactose.
 5. A formulation according to claim 4, in which the carrierparticles are of lactose.
 6. A formulation according to any one ofclaims 1 to 5, in which the carrier particles are of a material having afissured surface.
 7. A formulation according to any one of claims 1 to6, in which the carrier particles are of a crystalline sugar having atapped density not exceeding 0.75 g/cm³.
 8. A formulation according toclaim 7, in which the carrier particles have a tapped density notexceeding 0.7 g/cm³.
 9. A formulation according to any one of claims 1to 8, in which the carrier particles have a bulk density as measured bymercury intrusion porosimetry of not exceeding 0.6 g/cm³.
 10. Aformulation according to any one of claims 1 to 9, in which the carrierparticles are in the form of an agglomerate consisting of a plurality ofcrystals fused to one another.
 11. A formulation according to any one ofclaims 1 to 10, in which the carrier particles are obtainable by a wetgranulation process.
 12. A formulation according to any one of claims 1to 10, in which the carrier particles are dendritic spherulities.
 13. Aformulation according to any one of claims 1 to 12, in which theadditive material is present in an amount of not more than 50% by weightbased on the weight of the formulation.
 14. A formulation according toclaim 13, in which the additive material is present in an amount of notmore than 10% by weight based on the weight of the formulation.
 15. Aformulation according to claim 14, in which the additive material ispresent in an amount of not more than 5% by weight based on the weightof the formulation.
 16. A formulation according to any preceding claim,in which the additive material includes one or more compounds selectedfrom amino acids and derivatives thereof, and peptides and polypeptideshaving a molecular weight from 0.25 to 1000 Kda, and derivativesthereof.
 17. A formulation according to claim 16, in which the additivematerial comprises an amino acid.
 18. A formulation according to claim17, in which the additive material consists essentially of leucine. 19.A formulation according to any one of claims 1 to 17, in which theadditive material comprises a phospholipid or a derivative thereof. 20.A formulation according to claim 19, in which the additive materialcomprises soya lecithin.
 21. A formulation according to any one ofclaims 1 to is, in which the additive material comprises one or morecompounds selected from the group consisting of magnesium stearate,calcium stearate, sodium stearate, lithium stearate, stearic acid,stearylamine, sodium stearyl fumarate, oleic acid, starch, behenic acid,glyceryl behenate and sodium benzoate.
 22. A formulation according toclaim 21, in which the additive is magnesium stearate.
 23. A formulationaccording to any one of claims 1 to 15, in which the additive materialis selected from fatty acids and derivatives, waxes and oils.
 24. Aformulation according to any one of claims 1 to 23, in which theadditive material is in particulate form.
 25. A formulation according toclaim 24, in which at least 90% by weight of the additive particles havean aerodynamic diameter of less than 100 μm.
 26. A formulation accordingto claim 24 or claim 25, in which the mass median aerodynamic diameterof the additive particles is not more than about 10 μm.
 27. Aformulation according to any preceding claim, which comprises not lessthan 0.01% by weight of additive material based on the weight of theformulation
 28. A formulation according to any preceding claim, in whichthe additive material forms a discontinuous covering on the surfaces ofthe carrier particles.
 29. A formulation according to claim 28, in whichthe additive material, whilst forming a discontinuous covering on thesurfaces of the carrier particles, saturates the surfaces of the carrierparticles.
 30. A formulation according to any one of claims 1 to 29,which contains up to 90% by weight of active particles, based on thetotal weight of active particles, additive material and carrierparticles.
 31. A formulation according to claim 30, which contains up to50% by weight of active particles, based on the total weight of activeparticles, additive material and carrier particles.
 32. A formulationaccording to claim 31, which contains up to 20% by weight of activeparticles, based on the total weight of active particles, additivematerial and carrier particles.
 33. A formulation according to any oneof claims 1 to 32, which comprises at least 50% by weight carrierparticles, based on the total weight of the formulation.
 34. Aformulation according to claim 33, which comprises at least 70% byweight carrier particles, based on the total weight of the formulation.35. A formulation according to any one of claims 1 to 34, in which theactive particles comprise a therapeutically active agent for theprevention or treatment of respiratory disease.
 36. A formulationaccording to any one of claims 1 to 35, in which the active particlescomprise one or more active agents selected from β₂-agonists,ipratropium bromide, steroids, cromones and leukotriene receptorantagonists.
 37. A formulation according to claim 35, in which theactive particles comprise a therapeutically active agent having systemicactivity.
 38. A formulation according to any one of claims 1 to 37, inwhich the active particles comprise one or more agents selected frompeptides, polypeptides, proteins and DNA fragments.
 39. A formulationaccording to claim 38, in which the active particles comprise insulin.40. A formulation according to any one of claims 1 to 39, which furthercomprises fine particles of an excipient material of aerodynamicdiameter not more than 50 μm.
 41. A formulation according to claim 40,in which the mass median aerodynamic diameter of the fine excipientparticles is not more than 15 μm.
 42. A formulation according to claim41, in which the mass median aerodynamic diameter of the excipientparticles is not more than 10 μm.
 43. A formulation according to any oneof claims 40 to 42, which includes the fine excipient particles in anamount of not less than 4% by weight, based on the total weight of theformulation.
 44. A formulation according to any one of claims 40 to 43,including fine excipient particles in an amount of up to 20% by weight,based on the total weight of the formulation.
 45. A formulationaccording to claim 44, in which the fine excipient particles are presentin an amount of up to 15% by weight, based on the total weight of theformulation.
 46. A formulation according to any one of claims 40 to 45,in which the fine excipient particles are of dextrose or lactose.
 47. Aformulation according to claim 46, in which the fine excipient particlesare of lactose.
 48. A formulation according to any one of claims 40 to47, in which the carrier particles and the fine excipient particles areof the same material.
 49. A formulation according to any one of claims40 to 47, comprising up to 20% by weight fine excipient particles and upto 10% by weight additive material, based on the total weight of theformulation.
 50. A formulation according to any one of claims 1 to 49,which comprises up to 10% by weight additive material, based on thetotal weight of the formulation.
 51. A formulation according to anypreceding claim, which comprises up to 5% by weight additive material,based on the total weight of the formulation.
 52. A formulation for usein a dry powder inhaler, comprising more than 5%, and preferably morethan 10% by weight, based on the total weight of the formulation, ofparticles of aerodynamic diameter less than 20 μm, the formulationhaving a flowability index of 12 mm or less.
 53. A formulation for usein an inhaler device, comprising: from 5 to 90% by weight carrierparticles having a diameter of at least 50 μm and a mass median diameterof at least 175 μm; from 0.01 to 90% by weight of a therapeuticallyactive agent; from 0.01 to 50% by weight of an additive material whichis able to promote release of the active material on actuation of theinhaler device; in each case, by weight, based on the total weight ofthe carrier particles, active agent and additive material.
 54. Aformulation according to claim 53, which further comprises particles ofa fine excipient material in an amount of not more than 50% by weight,based on the total weight of the formulation.
 55. A formulationaccording to claim 53, in which the carrier particles are present in anamount not exceeding 70% by weight, based on the total weight of theformulation.
 56. A formulation according to any one of claims 53 to 55in which the total content of therapeutically active agent, additivematerial and, if present, fine excipient is at least 10% by weight basedon the total weight of the formulation.
 57. A formulation according toclaim 56, in which the total content of therapeutically active agent,additive material and, if present, fine excipient particles, is at least20% by weight, based on the total weight of the formulation.
 58. Aformulation substantially as described herein.
 59. A formulationsubstantially as described in any of Examples 1 to
 18. 60. An inhalerdevice comprising a formulation according to any one of claims 1 to 59.61. A device according to claim 60, which is a dry powder inhaler.
 62. Adevice according to claim 60, which is a pressurised metered doseinhaler.
 63. A method of manufacturing a formulation according to anyone of claims 1 to 59, comprising mixing the additive material with thecarrier particles and the active particles.
 64. A method according toclaim 63, in which the additive material is mixed with fine excipientmaterial before mixing with the carrier particles and the activeparticles.
 65. The use of fissured carrier particles of mass mediandiameter of at least 175 μm in combination with an additive material toincrease the fine particle fraction obtainable from a formulation for aninhaler device.